The Synthetic Routes of Lidamidine

Lidamidine is an important intermediate in the synthesis of various pharmaceuticals and Agrochemicals.
Its synthetic routes have evolved over the years, and various methods have been developed to synthesize this compound.
In this article, we will discuss the different synthetic routes of Lidamidine.

1. Classical Method
   The classical method of synthesizing Lidamidine involved the reaction of N-ethylmaleimide with malonic acid followed by hydrolysis of the resulting N-ethylmalonyl bisulfate.
   This method is relatively simple, but it has been replaced by more efficient methods.
   
2. Amidation Method
   The amidation method involves the reaction of malonic acid or its derivatives with N-bromoacetamide or N-chloroacetamide, followed by hydrolysis of the resulting N-bromo or N-chloro derivative.
   This method is more efficient than the classical method and is widely used in industry.
   
3. Direct Amidation Method
   The direct amidation method involves the reaction of malonic acid or its derivatives with N-alkyl or N-aryl iodides in the presence of a catalyst such as Hunig's base or pyridine.
   The resulting N-alkyl or N-aryl amidates are then hydrolyzed to give Lidamidine.
   
4. Ullmann Condensation Method
   The Ullmann condensation method involves the reaction of a substituted pyridine with an acyl chloride in the presence of a strong base such as sodium hydroxide or potassium hydroxide.
   The resulting pyridinium salt is then hydrolyzed to give Lidamidine.
   
5. Hydrolysis of N-substituted Maleimides
   The hydrolysis of N-substituted maleimides involves the reaction of N-alkyl or N-aryl maleimides with water in the presence of a catalyst such as HCl or H2SO4.
   The resulting Lidamidine can be further converted to other pharmaceuticals or agrochemicals.
   

In conclusion, Lidamidine can be synthesized through various methods, each with its advantages and disadvantages.
The choice of method depends on the availability of starting materials, the desired yield, and the purity of the product.
The amidation method is the most widely used method in industry, as it is more efficient and cost-effective than the classical method.